Imino-benzyl-pyrazoles

ABSTRACT

WHEREIN R is alkyl, cycloalkyl, phenyl, substituted phenyl or phenylalkyl, R1 is hydrogen, halogen, alkyl, trifluoromethyl, alkoxy, hydroxy or amino, R2 is alkyl, phenylalkyl or carbalkoxy, and R3 is hydrogen, alkyl, phenyl or substituted phenyl possess hypoglycemic activity.   Compounds of the formula

United States Patent 1 Bandurco et al.

[ 1 Jan. 30, 1973 IMINO-BENZYL-PYRAZOLES Inventors: Victor Bandurco,Huntington Station', James R. Shroff, Bronx, both of NY.

Assignee: U. S. V. Pharmaceutical Corporation Filed: Aug. 19, 1970 vAppl. No.: 65,304

US. Cl. ..260/310 R, 260/566 D, 260/999 Int. Cl. ..C07d 49/36 Field ofSearch ..260/310 R References Cited UNITED STATES PATENTS.

2/1960 Karmas et al. ..260/310 R 3/1960 ..260/310 R 11/1962 ..260/310 R4/1966 ..260/310 R Lynn Dvornik....

Primary ExaminerNatalie Trousof Attorney-Leon E. Tenenbaum [57] ABSTRACTCompounds of the formula 1? N/ R, ig-Q? 8 Claims, No DrawingslMlNO-BENZYL-PYRAZOLES This invention relates to new organic compoundshaving valuable pharmacological activity and to a process for thepreparation of said compounds. In particular, the invention relates toimino-benzyl-pyrazoles of the formula and their pharmaceuticallyacceptable, non-toxic'acid addition salts, wherein Y R is lower alkyl,phenyl, lower alkylphenyl, lower alkoxyphenyl, halophenyl, cycloalkyl,or phenyllower alkyl; I

R is hydrogen, lower alkoxy, lower alkyl, halogen,

trifluoromethyl, hydroxy, or amino;

R is lower alkyl, phenyl-lower alkyl, or carbalkoxy such as carbomethoxyor carbethoxy; and

R is hydrogen, lower alkyl, phenyl, halophenyl,

lower alkylphenyl, or lower alkoxyphenyl.

The lower alkyl and lower alkoxy groups may be branched orstraight'chained and contain from one to five carbon atoms. Thecycloalkyl groups contain from three to seven carbon atoms in the ringwhich may also carry a lower alkyl substituent.

Preferably, R is lower alkyl, phenyl or cyclohexyl, R is hydrogen orlower alkoxy, R is lower alkyl or carboalkoxy, and R is lower alkyl.

According to the process of this invention, the iminobenzyl-pyrazoleswere prepared by heating in an inert solvent an appropriatelysubstituted benzimidoyl chloride of the formula with an appropriatelysubstituted pyrazole of the formula Suitable inert solvents includehydrocarbons such as hexane, heptane, benzene, toluene and xylene,nitriles such as acetonitrile, and dimethylformamide.

The invention will be more fully illustrated in the examples thatfollow, which examples are given by way of illustration and are not tobe considered as limiting.

EXAMPLE I3-Carbomethoxy-I-[Z-methyl-(N-phenyliminobenzyl)]-5-(4-chlorophenyl)pyrazoleTo a suspension of 1.6 g. (0.048 mole) of 50% Nal-l in ml. dry distilleddimethyl-formamide, was added 7.8 g. (0.03 mole)3-carbomethoxy-5-(4-ehlorophenyl)-pyrazole over a period of 15 minutes.After the evolution of hydrogen gas had ceased, 7.6 g. (0.03

mole) of Z-methyl-N-phenylbenzimidoyl chloride was added dropwise intothe reaction mixture. The reaction mixture was heated to 100 for aperiod of 24 hrs., and then cooled. It was filtered and the 1 filtratewas evaporated in vacuum to remove the dimethylformamide. The residuewas dissolved in water and the organic material extracted with ether.Concentration of the dried ether layer yielded 6 g. of the crudeproduct. Two recrystallizations from n-heptane afforded 3-carbomethoxyl-[2-methyl-( N-phenyliminobenzyl)]-5-(4 -chlorophefiylj' i yraaole, m.p.138-40, in 17 pe rcerit yield (2.5 g.).

EXAMPLE ll 3-Carbomethoxyl -(N-ethyliminobenzyl )-5-methylpyrazole To amixture of 7.0 g. (0.05 mole) methyl 5-methylpyrazole-3-carboxylate and5.3 g. (0.05 mole) triethylamine in 75 ml. dry acetonitrile was added7.5 g. (0.05 mole) N-ethylbenzimidoyl chloride overa period of one-halfhr. After the addition was completed, the mixture was heated to refluxfor a period of 5 hrs. After the triethylamine hydrochloride was removedby filtration, concentration of the acetonitrile layer and distillationof the residue afforded 3-carbomethoxy-l -(N-ethyliminobenzyl)-5- methylpyrazole, b.p. l30-32 (1mm), n,,l.5539, in 37 percent yield (5.0 g.).

EXAMPLE lll 1-(N-Isobutyliminobenzyl)-3 ,S-dimethyl-pyrazole To asuspension of 7.8 g. (0.2 mole) sodamide in ml. dry toluene was added9.8 g. (0.1 mole) 3,5- dimethyl pyrazole dropwise over a period of 10min. The reaction mixture was heated to reflux for 3 hrs. and thencooled. To the cooled solution was added 19.5 g. (0.1 mole)N-isobutylbenzimidoyl chloride dropwise, and the resulting solutionrefluxed for 4 hrs. Two hundred ml. water was added to the reactionmixture and the organic layer separated from the aqueous fraction.Concentration of the dried toluene layer and distillation of the residue(25.0 g.) afforded l-(N-isobutyliminobenzyl)-3,5-dimethyl pyrazole, b.p.l02-6 (0.02 mm.), n 1.5390, in 43 percent yield l 1.0 g.).

In accordance with the procedures described above and set forth in theexamples, the following additional compounds were prepared.

i MP. or B.P./inm

' Cyclohex H Me Me 11810.05

Ph H Me Me l30-32/0.05 p-MeOc H, H Me Me 160-64/13 n-Pr H COOMe MelO4-10/0.l Me H COOMe Me l38-40/0.1 i-But p-Me COOMe Me l6062/0.25 i-Butm-C COOMe Me 12o/0.1 5 Ph H COOMe Me 99-100 i-But p-F COOMe Mel40-44/0.04 n-But H COOMe Me 142/02 i-Am H COOMe Me 120/008 Cyclohex HCOOMc Me 89-90 Ph o-McO COOMc Me 134-5 Ph o-Cl COOMc Me 118-20 Ph o-McCOOMc Me 104-7 p-MeC,H, p-Mc COOMe Me 1 116-18 h 3,4-(Cl), COOMe Me105-6 p-ClC,H, H COOMe Me 88-90 p-MeOC,H, H COOMe Me 70-72 p-MeOC.H, HCOOMe p-ClC,H, 140-42 p-MeC H pCH, COOMe -ClC.H, 147-50 h H COOMe-C1C.H, 187-8 Cyclohex H. COOMe p-ClC,H, 139-41 Me H COOMe p-CIC H114-16 n=normal Me=methyl 1=l80 Et=ethyl Fpara Pr=propyl m=meta BuFbutylPh=phenyl Amqmyl The compounds of this invention are potent hypoglycemicagents, producing a reduction of up to 34 percent in the blood sugar ofglucose primed rats when administered 100 mg./kg. p.o. The compounds canbe combined with solid or-liquid pharmaceutical carriers and formulatedinto tablets, powders or cap- 0 sules or dissolved in suitable solventsfor oral or parenteral administration.

We claim: l. A compound of the formula li 35 RAN/{3R1 wherein R is loweralkyl, phenyl, lower alkylphenyl or cycloalkyl of from three to sevencarbon atoms; R, is hydrogen, lower alkyl, lower alkoxy, halogen ortrifluoromethyl;

R, is lower alkyl or carbo-lower alkoxy; and R is lower alkyl, phenyl orhalophenyl. 2. A compound according to claim 1 wherein R is isobutyl R,is meta-trifluoromethyl, R is carbomethoxy, and R is methyl 3. Acompound according to claim 1 wherein R, is hydrogen or lower alkoxy; R,is methyl or carbomethoxy, and R, is lower alkyl. 4. A compoundaccording to claim 3 wherein R is ethyl; R, is hydrogen, and R and Raremethyl. 5. A compound according to claim 3 wherein R is phenyl; R, ishydrogen, and R and R are methyl. 6. A compound according to claim 3wherein R is eth l; R, is hyt lrogen; R is carbomethoxy, and R ismethyl. 7. A compound according to claim 3 wherein R is phenyl; R, ishydrogen; R is carbomethoxy, and R is methyl.

- 8. A compound according to claim 3 wherein R is cyclohexyl; R, ishydrogen; R is carbomethoxy, and R is methyl.

1. A compound of the formula
 2. A compound according to claim 1 whereinR is isobutyl R1 is meta-trifluoromethyl, R2 is carbomethoxy, and R3 ismethyl
 3. A compound according to claim 1 wherein R1 is hydrogen orlower alkoxy; R2 is methyl or carbomethoxy, and R3 is lower alkyl.
 4. Acompound according to claim 3 wherein R is ethyl; R1 is hydrogen, and R2and R3 are methyl.
 5. A compound according to claim 3 wherein R isphenyl; R1 is hydrogen, and R2 and R3 are methyl.
 6. A compoundaccording to claim 3 wherein R is ethyl; R1 is hydrogen; R2 iscarbomethoxy, and R3 is methyl.
 7. A compound according to claim 3wherein R is phenyl; R1 is hydrogen; R2 is carbomethoxy, and R3 ismethyl.